An effective therapeutic vaccine for HIV should be capable of reducing viral load and spread of infection and prevent the onset of AIDS. In an SIV-rhesus macaque model, immunization with a recombinant, soluble form of the human CD4 molecule (rsCD4) induced an anti-CD4 response that reduced viral load and rendered PBLs from the immunized animals resistant to infection with SIV. This anti-viral activity was found in the IgG fraction of the plasma. In a small Phase I clinical study HIV-infected individuals immunized with human rsCD4 in IFA developed an anti-CD4 response but levels achieved were insufficient to prevent spread of HIV. These results suggest that B cell tolerance to this protein can be overcome. This application will focus on developing strategies for enhancing immune responses to rsCD4 in an animal model tolerant to human CD4. In particular, a series of vaccines composed of vaccines composed of rhesus rsCD4, rsCD4- protein conjugates of CD4-derived peptide conjugates formulated in different adjuvants will be e valuated for their ability to enhance T helper and B cell responses in a mouse model expressing a human CD4 transgene. This study will permit the selection of a more immunogenic rsCD4 formulation for clinical study.